Molecular engineering of peptide-drug conjugates: strategies for enhancing precision oncology

Malignant neoplasms remain a formidable challenge to global public health, representing the second leading cause of mortality worldwide. While conventional small-molecule chemotherapeutics have historically served as a cornerstone of clinical oncology, their clinical utility is severely hampered by poor targeting specificity, systemic toxicities, and the evolution of complex resistance mechanisms. Although ADCs have been developed to enhance tumor targeting, their large molecular size significantly limits tissue penetration in dense solid tumors. Conversely, while PDCs offer superior tissue penetration due to their small size, they encounter significant translational hurdles, including rapid renal clearance, premature degradation in the bloodstream, and the lack of standardized industrial manufacturing protocols. This review systematically analyzes the molecular engineering strategies employed in PDC development, evaluating the design of functional peptides, versatile linkers, and diverse therapeutic payloads. It further synthesizes current insights into the mechanisms of action, pharmacokinetic optimization, and clinical translational challenges. The review identifies that the precise engineering of targeting and cell-penetrating peptides is essential for maximizing tumor specificity while minimizing off-target effects. It elucidates that stimulus-responsive linkers—designed to remain stable during systemic circulation but cleave within the tumor microenvironment—are critical for balancing safety and efficacy. Additionally, the integration of artificial intelligence for candidate screening and the adoption of novel strategies, such as albumin-binding motifs and in vivo self-assembly, are highlighted as effective solutions to extend circulatory half-life and improve tumor retention. Ultimately, the fusion of PDCs with other therapeutic modalities—most notably in radio-peptide conjugates—offers a promising strategy to overcome current limitations and elevate the efficacy of cancer theranostics. By bridging fundamental molecular design with industrial and clinical translational requirements, this review provides a robust framework for the rational development of next-generation PDCs in precision oncology.